Biochem. J. (2007) 404, 1–13 (Printed in Great Britain) doi:10.1042/BJ200701401REVIEW ARTICLESirtuins in mammals: insights into their biological functionShaday MICHAN and David SINCLAIR1Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA, U.S.A.Sirtuins are a conserved family of proteins found in all do-mains of life. The first known sirtuin, Sir2 (silent informationregulator 2) of Saccharomyces cerevisiae, from which the familyderives its name, regulates ribosomal DNA recombination, genesilencing, DNA repair, chromosomal stability and longevity. Sir2homologues also modulate lifespan in worms and flies, and mayunderlie the beneficial effects of caloric restriction, the onlyregimen that slows aging and extends lifespan of most classes oforganism, including mammals. Sirtuins have gained considerableattention for their impact on mammalian physiology, since theymay provide novel targets for treating diseases associated withaging and perhaps extend human lifespan. In this review wedescribe our current understanding of the biological functionof the seven mammalian sirtuins, SIRT1–7, and we will alsodiscuss their potential as mediators of caloric restriction andas pharmacological targets to delay and treat human age-relateddiseases.Key words: ADP-ribosyl transferase activity, caloric restriction,deacetylase activity, resveratrol, SIR2 (silent information regu-lator 2), sirtuin (SIRT1–7).DISCOVERY OF THE SIRTUINSIt is a little known fact that the first sirtuin gene, SIR2 fromSaccharomyces cerevisiae, was originally known as MAR1 (formating-type regulator 1). Klar and collegues [1] discovered MAR1by virtue of a spontaneous mutation that caused sterility byrelieving silencing at the mating-type loci HMR and HML.Avariety of additional mutations with a sterile phenotype wereco-discovered by Jasper Rine, who named the set of four genesresponsible SIR (silent information regulator)1–4 [2–4], therebyreplacing the MAR nomenclature.Gottlieb and Esposito [5] demonstrated, 10 years after thisinitial finding, that SIR2 is the only SIR gene required to suppressrecombination between the 100–200 copies of the ribosomal RNAgenes repeated in tandem on chromosome XII. By 1991, thanksprimarily to work by Gottschling and colleagues [6], SIR2 wasalso known to be part of the mechanism that silences genes neartelomeres. About 2 years later, Braunstein et al. showed that silentregions at telomeres and mating-type loci are associated withhistones that are relatively hypoacetylated at the ε-amino groupof N-terminal lysine residues [7]. SIR2 overexpression causedsubstantial histone deacetylation, an additional characteristic thatdistinguished SIR2 from the other SIR genes.In 1995, Brachman et al. [8] and Derbyshire et al. [9] dis-covered four additional S. cerevisiae genes with high homologyto SIR2, HST (homologues of SIR2)1–4. None of the fourgenes were essential, but they all were involved in silenc-ing at the mating-type loci and telomeres, as well as cell-cycleprogression and genomic integrity. The finding of SIR2 homo-logues in yeast and shortly thereafter in organisms ranging frombacteria to plants and mammals, demonstrated SIR2 is a mem-ber of a large and ancient family of genes we now refer to as‘sirtuins’.SIRTUINS ARE NAD+-DEPENDENT DEACETYLASES ANDMONO-ADP-RIBOSYL TRANSFERASESOver the next 2 years a variety of interesting features aboutSir2 were discovered: it localizes to the nucleolus [10], it is acomponent of the Ku-associated apparatus that repairs double-stranded DNA breaks [11], it localizes to DNA breaks in a check-point-dependent manner [12–14] and it silences marker genes andalters chromatin structure at the rDNA (ribosomal DNA) locus[15,16]. The first insight into Sir2 enzymatic activity came fromthe characterization of CobB, a Salmonella typhimurium pro-tein with nicotinate mononucleotide:5,6-dimethylbenzimidazolephosphoribosyl transferase activity. CobB contains a conserveddiagnostic feature of the sirtuins: the amino acid sequencesGAGISAESGIRTFR and YTQNID (conserved residues areunderlined) [17]. By 1999, Roy Frye had identified five of thehuman SIR2 homologues, SIRT1–5, given the name ‘sirtuins’, andfound that SIRT2 could act as an ADP-ribosyl transferase using,as a donor, one of the major nicotinamide nucleotides, NAD+.The transfer of an ADP-ribose from radioactively labelledNAD+to BSA, and the loss of catalysis when a highly conservedamino acid in the Sir2 homology domain (H171Y) was mutated,were both good indicators that this family of proteins might act asADP-ribosyl transferases [18]. Only a few months later, Moazedand colleagues [19] found that the yeast Sir2 had the ability tocovalently modify a mixture of histones and itself using NAD+as a donor, via the transfer of ADP-ribose to acceptor aminoacids. Accordingly, the analogous mutation in yeast, H364Y,Abbreviations used: AceCS1, acetyl-CoA synthetase 1 ; AFP, α-fetoprotein; CDC, cell division cycle; C/EBPα, CCAAT/enhancer-binding protein α;CR,calorie restriction; ERC, extrachromosomal circle; FOXO, Forkhead box class O; GDH, glutamate dehydrogenase; HEK, human embryonic kidney; HIC1,hypermethylated in cancer 1; HST, homologues of SIR2; IGF, insulin-like growth factor; MAR1, mating-type regulator 1; MEF2, MADS box transcriptionenhancer factor 2; MyoD, myogenic differentiation; NDRG1, N-Myc down-regulated gene 1; NF-κB, nuclear factor κB; Nmnat, nicotinate mononucleotideadenylyltransferase;OAADPr, 2-O-acetyl-ADP-ribose; PARP-1, poly(ADP-ribose) polymerase-1; PGC-1α, PPAR-γ co-activator 1α; PML, promyelocyticleukaemia; PPAR-γ, peroxisome proliferator-activated receptor γ; rDNA, ribosomal DNA; RNA Pol I, RNA polymerase I; SIR, silent information regulator;SIRT, sirtuin; STAC, sirtuin activating compounds; TAFI68, TBP-associated factor I 68; Tat, transactivator of transcription; TBP, TATA-box binding protein;TGF-β, transforming growth factor-β;TNFα, tumour necrosis factor α; TRPM2, transient receptor potential melastatin-related channel 2; UCP2, uncouplingprotein 2.1To whom correspondence should be addressed (email david [email protected]).cThe Authors Journal compilationc2007 Biochemical Societywww.biochemj.orgBiochemical Journal2 S. Michan and D. SinclairFigure 1 Sirtuin enzymatic activitiesSirtuins are NAD+-dependent deacetylases and mono-ADP-ribosyl transferases that regulate